The human MYH gene (“MYH”) encodes a protein involved in the DNA base excision repair pathway. It is the human homolog of the E. coli DNA repair gene mutY (mutY homolog: MYH). MYH encodes a DNA glycosylase involved in excising adenines misincorporated opposite 8-oxo-7,8-dihydro-2′-deoxyguanosine caused by the oxidative damage of guanine. If the defect is not repaired, G:C basepairs are mutated by transversion to T:A basepairs during DNA replication. The DNA sequence of the human MYH gene was described by Slupska et al. (J. Bacteriol. 178:3885-92 (1996)). The MYH gene has 16 exons, encodes a 535 amino acid protein, and is located on the short arm of chromosome 1, between p32.1 and p34.3.
Recently, MYH genetic variants were implicated in susceptibility to colorectal tumors in humans. Al-Tassan et al. (Nat. Genet., 30:227-32 (2002)) identified a family with individuals having multiple colorectal adenomas and carcinoma. Interestingly, this family lacked inherited mutations in the APC gene (Adenomatous polyposis coli), a major colorectal cancer predisposition gene. Inherited mutations in the APC gene are known to cause familial adenomatous polyposis (FAP), an autosomal dominant disorder characterized by hundred to thousands of colorectal adenomas, some of which progress to cancer.
Analysis of tumor DNA from members of the family showed overrepresentation of mutations in the APC gene that were G:C→T:A transversions, suggesting a problem with the DNA base excision repair pathway. Subsequent analysis of the MYH gene revealed 2 missense variants. Biochemical analyses of the variants were examined in the E. coli enzyme since the human enzyme is intractable. The biochemical analysis showed that the glycosylase activity was significantly reduced for the mutants. Thus, Al-Tassan et al. linked inherited variants in MYH to the pattern of somatic APC mutation in this family and implicated defective base excision repair in predisposition to tumors in humans.
Attenuated FAP (AFAP) is associated with less adenomas (5-100) and can be caused by inherited mutations in several regions of the APC gene. Sampson et al. (Lancet, 362:39-41 (2003)) found that a significant proportion (23%) of patients from 111 families having FAP and AFAP-like presentations had biallelic mutations in MYH.
Hereditary non-polyopsis colorectal cancer (HNPPC) is another cancer that is characterized by a family history of early onset colorectal cancer in the absence of florid polyposis (Peltomaki Hum. Mol. Gen., 10:735-740 (2001)). HNPCC is associated with deleterious mutations in the genes encoding the mismatch repair pathway enzymes, particularly in the MLH1 and MSH2 genes.
As MYH plays an important role in DNA base excision repair, mutations that result in alterations of MYH protein structure and/or biological activity can lead to an overall increase of mutation rate and are associated with predisposition to cancers. Thus, it is desirable to identify additional deleterious mutations in the MYH gene, which may serve as potential diagnostic markers and therapeutic targets.